Coagulation timing apparatus, and method

ABSTRACT

Apparatus for determining various blood coagulation times removes inaccuracies of prior apparatus by blanking first derivative signal for part of the coagulation time and then only comparing a component of said signal to a preset level to determine the clotting time.

United States Patent [151 3,658,480 Kaneet al. 1 Apr. 25, 1972 [54]COAGULATION TIMING APPARATUS, [56] References Cited A D ET D N M H0UNITED STATES PATENTS [72] Inventors: Gerald J. Kane, North Wales;Eugene J.

weaherby, Perkasie, both of Pa. 3,458,287 7/1969 Gross et al. ..73/64.lX [73] Assignee: Bio/Data Corporation, Norristown, Pa.PrimaryExaminerMorris O- Wolk Assistant Examiner-R. M. Reese 1 F I1ed= vl3, An0mey-Seidel, Gonda & Goldhammer [2!] App]. No.: 27,582 ABSTRACT QApparatus for determining various blood coagulation times [52] U.S.Cl...23/230 B, 230537522519, removes inaccuracies of prior apparatus byblanking first l 3 derivative signal for part of the coagulation timeand then only Int- Cl- ..G0 I] comparing a component of Said signal to apreset le el to [58] Field of Search ..23/23O B, 253; 73/64.]; determinethe clotting time.

BLANK/N6 CIRCUIT 10 Claims, 5 Drawing Figures COUNTEA" (TIMER) 3Sheets-Sheet 1 wm mm INVENTORS GERALD J. KANE EUGENE J. WEA THE/78)ATTORIVE rs \SUQG h bacxki m H w 9m E]! 7 3 mw\ 9w .QQW mm h wm mam H NMmm mm saw mw ww F ww Patented April 25, 1972 3,658,480

3 Sheets-Sheet z [[4] I I I l TIME SECONDS //v vt/v r005 GERALD J. KANEFla. 3 ggGENE J. WEA THERE? WM MI "1M.

A r rap/v5 rs Patented April 25, 1972 3,658,480

3 Sheets-Sheet 3 sEco/vos /O0 78/ 35 5 52 DIFF'El-P- COUNTER [NT/ALDIFFER- CIRCUIT E/vcE %54 AMPLIFIER 90 T Z4 v /04 /06 BLANK/N6 CIRCUITl/VVENTORS GERALD .1. KANE EUGENE .1.- W634 THE/PB) ATTORNEYSCOAGULA-TION TIMING APPARATUS, AND METHOD This invention relates to anapparatus and method for measuring various blood coagulation times. Moreparticularly, this invention relates to an automatic blood or plasmacoagulation timing apparatus and method for determining the bloodclotting time.

.The measurement of prothrombin and other blood or plasma coagulationtimes are well known laboratory procedures. Prothrombin time isdetermined by mixing known quantities of blood plasma with certainreagents and measuring the elapsed time between the mixing of thesolution and the commencement of clot formation. There are several usesfor the test as explained in the literature. For example, it isparticularly desirable to know the blood clotting time of persons underanti-coagulant therapy. The prothrombin time of the blood of individualsunder such therapy must be closely regulated both initially to determinethe correct dosage and throughout the treatment to detect possiblechanges.

There are several other well known types of tests and proceduresinvolving the coagulation of blood or plasma. Such tests have in commonthe singular fact that they all end in the coagulation or clotting ofblood.

The present invention is therefore directed to an apparatus and methodfor measuring the coagulation time in such tests. The precise laboratorytests are not described in detail as they are well known to thoseskilled in the art. It should be sufficient to simply refer to two testswhich difier primarily by the type of anti-coagulant in the plasma priorto the addition of a neutralizing reagent. When blood is drawn from apatient, it is drawn into either a citrated or an oxalatedanti-coagulant. The mixture of blood and anti-coagulant is convertedinto a plasma. Thereafter, it is tested to determine its coagulationtime. The reagent voids or neutralizes the effect of the bloodsanti-coagulant. One such test is the oxalate test because theanti-coagulant includes sodium oxalate. The other test may be referredto as the citrate test because of its use of citrated compounds.

There are several known devices for measuring coagulation times. Amongthese are the devices described in U.S. Pat. No. 3,307,392 issued toCharles A. Owen et al. and U.S. Pat. No. 3,458,287 issued to WilliamGross et al. U.S. Pat. No. 3,307,392 describes a rather rudimentarylight sensitive electronic circuit for measuring prothrombin time bydetermining the first differential of a signal proportional to the lighttransmitted through the mixture of blood and reagent. The devicedescribed in that patent depends upon the ability of the describedcircuit to sense when the first derivative signal proportional to theamount of light transmitted through the blood reaches a minimum, orreaches a maximum after a first minimum.

The prothrombin apparatus described in U.S. Pat. No. 3,458,287 carriesthe concept set forth in U.S. Pat. No. 3,307,392 to its logicalconclusion. Thus, it measures the second derivative'of a signalproportional to the amount of light transmitted through the blood, andmeasures when this second derivative signal changes sign. The apparatusdescribed in both U.S. Pat. Nos. 3,307,392 and 3,458,287 suffer fromcertain serious limitations. It is clear from examining the graphillustrated in these patents that the time constants of the exponentialcurves are extremely large. By the same token the time when thedifferential signal actually reaches a maximum (or minimum) isrelatively indefinite due to the slow change in the slope of the curve.Taking the second differential as in U.S. Pat. No. 3,458,287 is a steptoward solving the problem because it is relatively straightforward todetermine when the slope of the curve changes value from negative topositive. This approach, however, reduces the reliability in themeasurement of the clotting time. For example, U.S. Pat. No. 3,307,392makes it clear that coagulation time is not precisely known. Thus, thepatent points out that the end point can be measured either as the timewhen the first differential reaches a minimum value, or it can bemeasured when the first differential reaches a maximum after havingreached a first minimum. It also is known that coagulation (sometimesreferred to as end point time) can be somewhere in between the minimumand maximum values. Thus, coagulation time is actually a range of valuesand the selection of the particular value within that range is lefi opento choice by the analyst.

The present invention seeks to avoid the inadequacies of devicesconstructed according to U.S. Pat. Nos. 3,307,392 and 3,458,287 byretaining the selectivity of a first differential device while at'thesame time increasing accuracy and reliability in the measurement. Inaccordance with the present invention neither the first nor the seconddifferential is used to measure coagulation time. Rather, a component ofthe first differential is derived for comparison with a preselectedvalue.

It therefore is an object of the present invention to provide a new andunobvious coagulation timing apparatus, and method which is much morereliable than previous known apparatus for the same purpose. Previousapparatus is particularly unreliable when used to determine coagulationtime over extended period; e.g., 30 seconds. Other prior art devicesfailto consider the extremely long time constants from the signals beingmeasured. As a result, such circuits lack the requisite sensitivity andare inaccurate.

The present invention provides a coagulation timing apparatus which ismuch more sensitive. For example, existing apparatus indicates clottingtimes of l l to 15 seconds for normal blood plasma. Because the presentinvention is so much more sensitive, it indicates clotting times for thesame blood at 10 I 0.5 seconds from the low end of the range. This isbecause the apparatus has a higher sensitivity and is able to determinethe beginning of the formation of the blood clot at its insipiencey.

For the purpose of illustrating the invention, there is shown in thedrawings a form which is presently preferred; it being understood,however, that this invention is not limited to the precise arrangementsand instrumentalities shown.

FIG. 1 is a schematic circuit diagram of a preferred means for carryingout the present invention.

FIG. 2 is a graph illustrating electrical values generated in thecircuit of FIG. 1.

FIG. 3 is a graph illustrating electrical values generated in thecircuit of FIG. 1.

FIG. 4 is a family of curves derived from a timing apparatus.

FIG. 5 is a modification to the timing apparatus.

Referring now to FIGS. 2 and 3 of the patent application, there areshown two graphs illustrating the various signals which may be developedin the circuit illustrated in FIG. 1. These graphs best illustrate theunderlying concept of the present invention.

FIG. 2 graphically illustrates curves which may be generated by thecircuit illustrated in FIG. 1 when the test is made on plasma having anoxalate anticoagulant. Each curve on the graph represents a plot ofvoltage versus time made on a strip chart recorder. The plot marked Arepresents the output of a photosensitive device such as a photoresistorwhich generates a voltage signal proportional to the quantity of lightincident upon it. Ignoring the first portion of the curve A, it isapparent that it has a slow, smooth rise for a certain amount of time.Then it reverses and rapidly decreases. Then the slope reverses again tobecome asymptomtic to a fixed level. In both cases the changes in theslope of the curve A are relatively smooth with the first reversal beingindicative of the clotting time and occurring at about 13.6 seconds.

The curve B represents the first derivative of the curve A. This showsthat the end point time indicated by changes in the slope of the curveof the first derivative (B-1 and 8-2 in FIG. 2) are smooth rather thanabrupt. This is particularly true of the point noted as B-l in.FIG. 2.These points are therefore rather difiicult to accurately measure. CurveC in FIG. 2 represents the output voltage of the circuit of FIG. 1, andis discussed in detail below. The end point time is indicated at C-l. Itshould be noted that this end point time is rather abrupt in comparisonto the end point time indicated by curve B at B-l. The scale of theordinate for curves B and C is identical. Of course, the time scale forall three curves (A, B and C) is the same.

FIG. 3 contains the same curves as those developed for FIG. 2 exceptthat these curves plot the result of adding reagent to citrated bloodplasma. In this case the problem is even greater than that encounteredwith an oxalate plasma. As shown, the curve D representing the output ofthe photocell is substantially smoother and so are the changes in thevoltage levels indicative of clotting such as at D-l. Because of thesmoothness of the curve D, the curve B also is quite smooth even at thepoints 15-1 and E-2 which indicate the end point time. Moreover, curvessuch as D and E are much more prone to reflect interference (noise) inthe electrical circuitry as well as other disturbances caused byturbulence, as indicated in the early portion of the curves. Thus,reading the first derivative of a citrate curve of optical density isquite difficult.

The curve F represents the output of the circuit illustrated in FIG. 1.It will be noted that the end point time F-l is quite sharp andpronounced in comparison with the points E-l and E-2 therefore making itsubstantially easier to read and/or detect.

Referring now to FIG. 1, there is illustrated a circuit for detectingthe curves C and F and measuring coagulation time.

As shown, a test tube 12 or other container for a mixture of plasma andreagent is positioned by any conventional means such as the bracket 14between a source of electromagnetic energy 16 (preferably light) and anelectromagnetic transducer 18 (preferably a photoelectric device). Inthe preferred embodiment, the source 16 is an incandescent lamp and thetransducer 18 is a photoresistor. The light source 16 and transducer 18are properly matched so as to produce an appropriate response. Thecurves A and B represent the voltage output of the photocell 18. Thisvoltage output is connected into the circuitry by any conventional meanssuch as the coaxial cable 20.

The voltage output signal developed from the photocell 18 and resistor22, connected to the positive side of a direct current voltage supply,is filtered of AC noise and hum by resistor 24 and capacitor 26. Thesignal at capacitor 26 is differentiated in a differentiating circuitwhich includes resistor 200 and capacitor 28. As shown capacitor 28 andresistor 30 are connected to back-to-back diodes 32 and 34 which in turnare connected through resistor 38 to ground. Resistor 30 and capacitor202 along with resistor 204 and capacitors 206 and 208 limit the highfrequency gain of the amplifier configuration. The manner in which theabove described circuit functions as a differentiating circuit is wellknown and need not be described in detail. It is sufficient to point outthat the voltage signal which appears across the input terminals of theoperational amplifier 36 is the first differential of the voltage versustime curves developed by the photocell 18.

As shown, power for the amplifier 36 is provided from the positiveterminal of a direct current power supply (not shown) through resistor40 and conductor 42. The negative terminal of the direct current powersupply is connected through resistor 44 and conductor 46 to theoperational amplifier 36. Appropriate alternating current groundingmeans in the form of capacitors 47 and 48 are provided as shown. Theoperational amplifier 36 is provided with conventional feedback andcontrol circuitry which, therefore, need not be described in detail. Ahigh gain is necessary because the time constant of the signal is solarge that the differentiating circuit greatly attenuates the signal.The amplifier 36 also provides a good linear gain for'the differentiatedsignal.

The amplified and time changing output voltage of operational amplifier36 is coupled through capacitor 50 and appropriate limiting resistors 52and 54 to the base of transistor 56. The purpose of capacitor 50 is toremove the DC portion of the output signal of amplifier 36. Thus, theamplifier 36 due to its input effect characteristic has a 1 volt directcurrent level which must be removed. For this reason, the signal iscapacitively coupled into the base of transistor 56. Transistor 56 formsone half of a difference amplifier whose function is to amplify theinput signal. The other half of the amplifier consists of transistor 58whose base is connected to potentiometer 60. Potentiometer 60 provides areference voltage level against which the signal coupled from amplifier36 is matched.

The emitters of transistors 56 and 58 are commonly connected throughresistor 62 to the negative terminal of the power supply. The collectorof transistor 56 is connected to the base of transistor 64. Thecollector of transistor 58 is connected to the emitter of transistor 64.The collector of transistor 58 is also connected through resistor 66 tothe positive terminal of the power supply. The base of transistor 64 isconnected through resistor 68 to the positive terminal of the powersupply. The collector of transistor 64 is connected through resistor 70to ground. The emitter of transistor 64 is connected in series toresistor 72 to the base of transistor 74.

The circuitry described immediately above measures the difference involtage levels at the bases of transistors 56 and 58. When the voltageat the base of transistor 56 becomes greater than the preselectedvoltage level at the base of transistor 58, transistor 64 biasestransistor 74 into a conducting condition. When the voltage level at thebase of transistor 56 is less than the voltage level at the base oftransistor 58, transistor 64 biases transistor 74 off. Thus, transistor74 is normally biased into a non-conducting or off condition bytransistor 64 which in turn is controlled by the voltage differencesapplied to the difference amplifier. Transistor 64 is biased so as tosaturate quickly when the voltage level at the base of transistor 56 isgreater than the voltage level at the base of transistor 58. This ineffect converts the difference signal into a square wave. Such a squarewave signal is advantageous because of its quick rise time which can beused to trigger timing circuits as explained below.

The emitter of transistor 74 is connected to ground as shown. Thecollector is connected through resistor 76 to a direct current source ofvoltage which in the preferred embodiment is somewhat lower than theprimary supply voltage provided to the amplifier 36, as indicated.

The turning on of transistor 74 generates a voltage pulse which isapplied to a flipflop circuit in counter 78. Counter 78 is preferably adigital counter which is set in operation when a reagent is added totest tube 12. Thus, counter 78 indicates the amount of time expireduntil the voltage applied to the base of transistor 56 rises above apredetermined level. As explained below, this amount of time is the endpoint or coagulation time. It should be understood that the counter 78is but one example of a number of timing devices which may be used. Forexample, a strip chart recorder could be substituted for the counter andthe control circuitry thereof.

As shown, the base of transistor 56 is also connected to thecollector-emitter junction of back-to-back connected transistors 80 and82 which form a solid state switch. The other collector-emitter junctionof the transistors 80 and 82 is connected to ground. The bases oftransistors 80 and 82 are connected through like resistors 84 and 86 toone terminal of resistor 88. Resistor 88 is in turn connected to apositive terminal of the power supply at a somewhat lower voltage thanthe voltage applied to amplifier 36. Resistors 84 and 86 are alsoconnected to a blanking circuit 90 which, when energized, combines withthe voltage from the power supply to saturate the transistors 80 and 82and thus ground the base of transistor 56.

The blanking circuit 90 generates a blanking voltage to saturatetransistors 80 and 82 for a predetermined amount of time and then shutsdown so as to remove that voltage. Upon removal of the blanking voltagefrom transistors 80 and 82, the base of transistor 56 is no longerclamped to ground voltage. As a result, the voltage applied to the baseof transistor 56 becomes the output time changing voltage of operationalamplifier 36. Blanking circuit 90 is conventional in that it consists ofan integrated circuit timer for controlling an appropriate drivingvoltage. When the timer reaches a predetermined count, the blankingvoltage is removed.

The function of the blanking circuit is best illustrated by observingcurves C and F in FIGS. 2 and 3, respectively. As shown, curve C is heldat a fixed voltage (ground) for approximately 9 seconds. In a likemanner curve F is shown held at ground voltage for approximately 9seconds and then released. The advantage of holding these curves atground voltage is to avoid circuit transients created by the initialturbulence when the reagent is first added to the plasma. Thus, theoutput voltage is given an opportunity to settle down to a reasonablysteady value which is well below the voltage level set into the base oftransistor 58 by potentiometer 60. It has been found that 9 seconds issufficient amount of time to accomplish this function.

As shown in FIG. 1 potentiometer 60 is connected between ground andresistors 92 and 94. Resistor 92 is connected to capacitor 96 which inturn is connected to ground. In a like manner, resistor 94 is connectedto capacitor 98 which is connected to ground. Capacitors 96 and 98filter out noise from the circuit. Switch 100 connects either resistor92 or resistor 94 in series with potentiometer 60 and to the powersupply for appropriately biasing the base of transistor 58. Asindicated, the resistor 92 provides a gross adjustment for use of theapparatus with an oxalate plasma. Resistor 94 provides a grossadjustment for use of the circuit 10 with a citrate plasma. Fineadjustment is provided by potentiometer 60.

From the foregoing it should be apparent that the apparatus described inFIG. 1 provides a new and unobvious means and method for measuring bloodcoagulation time. In operation, the test tube 12 is positioned betweenthe source 16 and photocell l8. Thereafter a reagent is added to theplasma within the test tube and a start switch (not shown) issimultaneously operated. The start switch may be part of an automaticpipette used to add plasma to the reagent (or reagent to the plasma).The output voltage of photocell 18 is dif-' ferentiated, amplified andapplied to the base of transistor 56. However, blanking circuit 90together with the back-to-back transistors 80 and 82 hold this voltageat ground or some other preselected steady state value during theinitial portion of the coagulation time period. After the initial periodthe blanking circuit 90 removes the saturating voltage from thetransistors 80 and 82. This initial time period is preferablyapproximately 9 seconds although it may be adjusted as desired.Thereafter, the voltage applied to the base of transistor 56 is a timechanging voltage as coupled in by capacitor 50. However, the nature ofthe difference amplifier comprising transistors 56 and 58 is such thatit only reads the difference level of the voltage applied to the base oftransistor 56. Thus, the circuit avoids the problem of evaluating theslow changing curve representing the first differential of the photocellvoltage. When the voltage level applied to base 56 exceeds thepredetermined voltage value applied to the base of transistor 58,transistor 74 conducts, a square wave voltage is generated and counter78 turns off. Counter 78 thereafter can be read to determine thecoagulation time.

As previously stated, a circuit constructed in accordance with theforegoing principles is capable of detecting the clotting time with moreaccuracy and much earlier than previously known apparatus. By holdingthe level applied to the difference amplifier at zero for apredetermined amount of time, all turbulence and other extraneousfactors are removed from the curve. Thus, when the timer is triggered toan off condition, the user can be certain that the actual clotting timerather than some extraneous factor has been measured. Moreover, there isno need to be concerned with whether the signal is going from positiveto negative or negative to positive.

Referring now to FIG. 4, there is shown a family of curves 6-] G-9representing the signal applied to the base of transistor 56. Thissignal, it should be noted, decreases in amplitude as time progresses.Thus, the end point time for normal blood in a 10 to second range ismuch easier to detect than the end point time for blood in the 50 secondrange where the amplitude of the signal is so much lower. This is ofcourse a direct result of the fact that the change in the opticaltransmission quality of the blood plasma at the end point time is muchsmaller than for normal blood. The curvage drawn tangent to the familyof curves G-l G-9 illustrates how the level of the signal decreases at asubstantially asymptotic rate. Moreover, it should. also be noted thateach of the signals G-l G-9 is a rather quick rise time.

Because of the reduction in signal intensity, it is advantageous tostart with a rather high level signal at the base of transistor 58 andthen successively reduce that level as time progresses. Thus, thecircuit is made even more accurate in measuring signal levels for longcoagulation times.

The circuit illustrated in FIG. 5 provides such a means for reducing thelevel of the voltage applied to the base of transistor 58. Since thecircuit incorporates substantial portions of what is illustrated in FIG.1, only so much as is necessary to explain the modification isillustrated.

As shown, the output of the differentiating circuit is amplified by theamplifier 36 and coupled to the difference amplifier 100 by thecapacitor 50. In a like manner, the blanking circuit applies a signalthrough the saturated control switch 102 as previously explained withrespect to the circuit illustrated in FIG. 1. Moreover, the differenceamplifier is substantially the same as that illustrated in FIG. 1 withthe exception that the voltage level control applied to the base oftransistor 58 is now derived in the counter 78.

In the preferred embodiment, the counter 78 is a four stage binarycounter such as is well known in the art. Such a binary counter mayconsist of four decade counters controlling BCD to decimal drivers as iswell known in the art. The voltage output of each stage of the binarycounter can be applied successively to series connected resistors 104 soas to continuously drop the voltage level as the count progresses. Thenet result is a step-like asymptotic signal. This signal can be appliedto the capacitor 106 so that a rather smooth asymptotic curve similar tothe curve H in FIG. 4 is applied to the difference amplifier 100. As aresult, the voltage level which must be exceeded by the signal derivedfrom amplifier 36 is successively reduced as time progresses. Thus, thecircuit becomes much more sensitive for longer clotting times asrequired.

The present invention may be embodied in other specific forms withoutdeparting from the spirit or essential attributes thereof and,accordingly, reference should be made to the appended claims, ratherthan to the foregoing specification as indicating the scope of theinvention.

We claim:

1. Apparatus for determining coagulation time of blood plasma comprisinga source of light, a transducer responsive to said light, means forpositioning said plasma between said source and said transducer,differentiation means for dif ferentiating the signal output of saidtransducer, amplifying means for amplifying the differentiated signal, adifference amplifier, means for generating a comparison signal, saidcomparison signal being coupled into said difference amplifier, meansfor coupling a time changing component of the amplified differentialsignal into said difference amplifier, means for holding said componentbelow the level of said comparison signal for a preset amount of timeand then releasing said signal, and means to indicate coagulation timeresponsive to the output signal of said difference amplifier when thevalue of said component exceeds the value of the comparison signal.

2. Apparatus for determining coagulation time of blood plasma inaccordance with claim 1 wherein said means responsive to the outputsignal of said difference amplifier comprises means for generating asignal to stop a timer.

3. Apparatus for determining coagulation time of blood in accordancewith claim 1 wherein said means for holding said component below saidcomparison signal comprises a blanking circuit and switch for holdingsaid component at ground potential.

4. Apparatus for determining coagulation time of blood in accordancewith claim 3 wherein said means for holding said component below saidcomparison signal value for a preset amount of time and then releasingsaid signal includes a timer,

said timer being set to time out and release said component of a signalafter initial disturbances in the differentiated signal have ceased.

5. Apparatus for determining coagulation time of blood plasma inaccordance with claim 1 wherein said means for generating a comparisonsignal includes means for adjusting the comparison signal value as afunction of time.

6. Apparatus for determining coagulation time of blood plasma inaccordance with claim 5 wherein said means for generating a comparisonsignal includes means for presetting the comparison value depending uponthe type of reagent mixed with the blood plasma at the commencement ofthe timing period.

7. A method for determining coagulation time of blood plasma comprisingthe steps of passing light through a mixture of blood plasma andreagent, sensing the light so passed through the blood plasma andreagent, transducing the light so sensed into an electric signal,differentiating said electric signal, sensing a time changing componentof said signal, comparing said component of said signal to a comparisonsignal, and measuring the time it takes for the value of said componentof said differentiated signal to exceed said comparison signal.

8. A method for determining coagulation time of blood plasma inaccordance with claim 7 including the steps of successively changing thecomparison signal as a function of time.

9. Apparatus for determining coagulation time of blood plasma comprisinga source of light, a transducer responsive to said light, means forpositioning said plasma between said source and said transducer,differentiating means for differentiating the signal output of saidtransducer, amplifying means for amplifying the differentiated signal, adifference amplifier, means for generating a comparison signal, saidcomparison signal being coupled into said difference amplifier, meansfor coupling a time changing component of the amplified differentialsignal into said difference amplifier, and means to indicate coagulationtime, said means to indicate coagulation time being responsive to theoutput signal of said difference amplifier when the value of saidcomponent exceeds the value of the comparison signal.

10. A method for determining coagulation time of blood plasma comprisingthe steps of passing light through a mixture of blood plasma andreagent, sensing the light energy so passed through the blood plasma andreagent, transducing the light so sensed into an electric signal,difierentiating said signal, sensing a time changing component of saidsignal, and determining the coagulation time of the blood plasma bysensing when said time changing component of said signal exceeds apredetermined value.

2. Apparatus for determining coagulation time of blood plasma inaccordance with claim 1 wherein said means responsive to the outputsignal of said difference amplifier comprises means for generating asignal to stop a timer.
 3. Apparatus for determining coagulation time ofblood in accordance with claim 1 wherein said means for holding saidcomponent below said comparison signal comprises a blanking circuit andswitch for holding said component at ground potential.
 4. Apparatus fordetermining coagulation time of blood in accordance with claim 3 whereinsaid means for holding said component below said comparison signal valuefor a preset amount of time and then releasing said signal includes atimer, said timer being set to time out and release said component of asignal after initial disturbances in the differentiated signal haveceased.
 5. Apparatus for determining coagulation time of blood plasma inaccordance with claim 1 wherein said means for generating a comparisonsignal includes means for adjusting the comparison signal value as afunction of time.
 6. Apparatus for determining coagulation time of bloodplasma in accordance with claim 5 wherein said means for generating acomparison signal includes means for presetting the comparison valuedepending upon the type of reagent mixed with the blood plasma at thecommencement of the timing period.
 7. A method for determiningcoagulation time of blood plasma comprising the steps of passing lightthrough a mixture of blood plasma and reagent, sensing the light sopassed through the blood plasma and reagent, transducing the light sosensed into an electric signal, differentiating said electric signal,sensing a time changing component of said signal, comparing saidcomponent of said signal to a comparison signal, and measuring the timeit takes for the value of said component of said differentiated siGnalto exceed said comparison signal.
 8. A method for determiningcoagulation time of blood plasma in accordance with claim 7 includingthe steps of successively changing the comparison signal as a functionof time.
 9. Apparatus for determining coagulation time of blood plasmacomprising a source of light, a transducer responsive to said light,means for positioning said plasma between said source and saidtransducer, differentiating means for differentiating the signal outputof said transducer, amplifying means for amplifying the differentiatedsignal, a difference amplifier, means for generating a comparisonsignal, said comparison signal being coupled into said differenceamplifier, means for coupling a time changing component of the amplifieddifferential signal into said difference amplifier, and means toindicate coagulation time, said means to indicate coagulation time beingresponsive to the output signal of said difference amplifier when thevalue of said component exceeds the value of the comparison signal. 10.A method for determining coagulation time of blood plasma comprising thesteps of passing light through a mixture of blood plasma and reagent,sensing the light energy so passed through the blood plasma and reagent,transducing the light so sensed into an electric signal, differentiatingsaid signal, sensing a time changing component of said signal, anddetermining the coagulation time of the blood plasma by sensing whensaid time changing component of said signal exceeds a predeterminedvalue.